Diabetes mellitus Etiology and pathogenesis Clinical forms Nóra Hosszúfalusi 27.03.2017.
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Prevalence of diabetes mellitus type 2 in various racial and ethnic groups in the US (2007 estimates)
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Chronic complications of diabetes
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• Etiology, pathomechanism, diagnosis, classification • Diabetic complications • Treatment
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Diabetes mellitus • Sustained elevation of blood sugar (blood glucose, BG) • Cause: lack of insulin action - missing or impaired insulin production - impaired insulin effect • Acute and chronic complications 5
Effects of insulin on blood glucose (liver, muscle, fat) Inhibition
Enhancement
Major effects of insulin • Metabolic effects of insulin - inhibition of glycogenolysis and gluconeogenesis (liver) - enhance peripheral glucose uptake and utilization (muscle, fat) - restain lipolysis and proteolysis (fat, muscle) • Mitogenic effect
Mechanisms of hyperglycemia in diabetes
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Histology of normal pancreas
9 Adapted from and available at: http://pathologyoutlines.com/pancreas.html. Accessed February 28, 2006.
Pancreatic islet (islet of Langerhans)
~ 3,000 cells 200 µm 75% beta-cells 25% other (A,D,PP) cells
Micrograph: Lelio Orci, Geneva
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Beta cell
~ 10,000 10 µm granules
Micrograph: Lelio Orci, Geneva
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12 Florez J.C.: Diabetologia, 2008, 51, 1100-1110.
Putative mechanisms of insulin secretion
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The molecular basis of insulin resistance
PKC
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Symptoms of diabetes The blood sugar level exceeds the renal threshold of glucose (BG ≥ 10.0 mmol/l): • frequent urination with increased amount of urine = polyuria • intense thirst = polydipsia • loss of body weight fatigue, skin and mucosal infections, blurred vision (osmotic swelling of lenses) • Acute hyperglycemic crisis: diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS)
Diagnostic criteria of disturbances of carbohydrate metabolism (WHO 1998, ADA 2015) Diagnosis
Fasting blood glucose (mg/dl, mmol/l)
OGTT 120’ (mg/dl, mmol/l)
Normal carbohydrate tolerance
≤ 110, ≤ 6.0 (ADA < 100, 5.6)
< 140, < 7.8
(HbA1c < 5.7%) Impaired fasting glucose (IFG)
≤ 110 and ≤ 125 6.1-6,9 (ADA 100-125)
< 140, < 7.8
Impaired glucose tolerance (IGT)
< 126 , < 7.0
≥ 140 and < 200 7.8-11.0
Diabetes mellitus HbA1c ≥ 6.5%
≥ 126, ≥ 7.0
≥ 200, ≥ 11.1
Prediabetes HbA1c: 5.7-6.4 %
Diagnostic criteria of diabetes mellitus (WHO) Symptoms •
•
•
•
(polyuria, polydipsia, weight loss, DKA, HHS) + Random blood glucose level ≥ 11.1 mmol/l (≥ 200 mg/dl) or Fasting blood glucose level ≥ 7.0 mmol/l (≥ 126 mg/dl), (no caloric intake 8 h) or 120 min blood glucose in OGTT ≥ 11.1 mmol/l (≥ 200 mg/dl) or HbA1c ≥ 6.5 %
Diagnostic criteria of diabetes mellitus (WHO)/2.
• Without typical symptoms (screening) abnormal blood sugar value must be present on two occasions (on different days) • Personal blood sugar measuring devices are not allowed for diagnostic purposes: laboratory measurement is necessary. 18
Diagnostic criteria of diabetes mellitus (ADA, 2015) • HbAc1 ≥ 6.5 % or • Fasting blood glucose level ≥ 7.0 mmol/l (≥ 126 mg/dl) or • 120 min blood glucose in OGTT ≥ 11.1 mmol/l (≥ 200 mg/dl) • Same test repeat immediately • Symptoms (polyuria, polydipsia, weight loss, DKA, HHS) + • Random blood glucose level ≥ 11.1 mmol/l (≥ 200 mg/dl)
Screening for undiagnosed type 2 diabetes (ADA, 2015) • BMI ≥ 25 kg/m2 (Asian Americans ≥ 23 kg/m2) and one or more additional risk factors for diabetes at any age without risk factors testing should begin at age 45 years • Normal test → repeat at 3-year intervals • A1C, FPG, or 2-h OGTT • Diagnosis of DM → identify other CV risk factors • Children and adolescents overweight or obese and ≥ 2 risk factors for diabetes 20
Classification of diabetes • Type 1 diabetes results from beta cell destruction, leading to absolute insulin deficiency • Type 2 diabetes results from a progressive insulin secretion defect on a background of impaired insulin function impaired incretin function • Gestational diabetes mellitus (diagnosed during pregnancy) • Other specific types of diabetes (due to other known causes) 21
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CLASSIFICATION of diabetes (ADA 2017) CLASSIFICATION Diabetes can be classified into the following general categories:
• 1. Type 1 diabetes (due to autoimmune b-cell destruction, usually leading to absolute insulin deficiency) • 2. Type 2 diabetes (due to a progressive loss of b-cell insulin secretion frequently on the background of insulin resistance) • 3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation) • 4. Specific types of diabetes due to other causes, e.g., monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young [MODY]), diseases of the exocrine pancreas (such as cystic fibrosis), and drug- or chemical-induced diabetes (such as with glucocorticoid use, in the treatment of HIV/AIDS, or after organ transplantation) 23
Type 1 diabetes mellitus
• A. Autoimmune: autoimmune destruction of beta cells - rapid progression - slow progression (latent autoimmune diabetes in adults, LADA) • B. Idiopathic
Type 1 Diabetes Mellitus • • • •
Genetic susceptibility Triggering effect Period of immunologic abnormalities Manifestation of diabetes mellitus
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Islet of Langerhans Normal
Insulitis
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Genetic susceptibility Prevalence of T1DM
Average population before then age of 30 years
%
0,1-0,4
In case of diabetic sibling
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In case of diabetic parent
3-6
If the father is diabetic by the age of 20 years
6-9
If the mother is diabetic by the age of 20 years
1-4
In identical twins is diabetic by the age of 30 years
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In identical twins 12 years later after the diagnosis of the proband
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In identical twins 40 years later after the diagnosis of the proband
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In non-identical twins
10-12
HLA identical sibling
15 9
HLA haploidentical sibling HLA non-identical sibling
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1-2
30
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Predisposing HLA haplotypes and genotypes for T1DM • • • •
HLA DR4-DQ8 HLA DR3-DQ2 HLA DR4-DQ8/HLA DR3-DQ2 HLA DR4-DQ8/HLA DR4-DQ8
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Putative autoantigens • insulin (proinsulin) • GAD65 (glutamic acid decarboxylase) • IA-2 (homology with tyrosine phosphatases)
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Environmental factors • Enteroviruses (Coxsackie-B4, polio,) Antibody titer anti-CB4 is higher in DR3/DR4 > DR2, it means a lower cellular reaction to the virus, it could mean a persistent virus carrier status CMV • Bovine milk proteins (?) • Nitrosourea compounds (?) • Insufficient D3 vitamin supply(?) 34
Autoantibodies in T1DM Markers • ICA(islet-cell /cytoplasmatic/ autoantibodies) • GADA (autoantibody to glutamic acid decarboxylase ) • IA-2A (autoantibody to IA-2) • IAA (insulin autoantibodies) • ZnT8A (cink transzporter ZnT8 elleni antitest, kation pumpa /efflux/ család)
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Insulin response to IVGTT in healthy subjects and in subjects with ongoing beta cell damage Normal
Before T1DM 120 Plasma ma IRI (µU/ml)
Plasma ma IRI (µU/ml)
120 100 80 60 40 20 0 –30
0
30 60 90 120
Time (minute)
Ward WK et al. Diabetes Care 1984;7:491–502
100 80 60 40 20 0 –30
0
30 60 90 120
Time (minute)
Temporal model for development of T1DM
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Characteristics of T1DM • • • • • •
Classical clinical symptoms Ketonuria (Lack of obesity) Low C-peptide level Presence of autoantibodies Presence of other organ specific autoimmune disorders (thyroid, celiac, Addison) • Family history of T1DM, (predisposing HLA haplotypes) 38
Type 2 Diabetes Mellitus Two simple questions: Why do people get it (etiology)? What goes wrong (pathophysiology)? The answers are not simple!
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Reports of high and low rates of T2DM Low rates Poor of London and Berlin before 1900 Eskimos Rural poor of India Affluent societies during famine and war Rural Africans on traditional diet High rates Rich Indian men of Bengal Pima Indians Sephardic Jews of Zimbabwe Sumo wrestlers of Japan Royal families of Zululand Genetic influence (inter bred societies); environmental influences (poverty and affluence); combination of the those (Pima Indians on poor western diet) 40
Risk factors for T2DM • • • • • • • • • •
Family history of T2DM (parent or sibling with T2DM) Obesity (BMI 25 kg/m2) Sedentary lifestyle Race/ethnicity (African/Hispanic/Native/Asian Americans) Previously identified IFG or IGT History of GDM or delivery of baby > 4 kg Hypertension Dyslipidemia Polycystic ovary syndrome or acanthosis nigricans History of vascular disease
Obesity is a risk factor of T2DM
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Diet with decreased carbohydrate and increased fat content is characteristic for patients with T2DM. 44
UKPDS showed that obesity predominate at the diagnosis of T2DM.
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Skin abnormalities in insulin resistance • Acanthosis nigricans
• Fibroma
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Pathophysiology of T2DM • • • •
Peripheral insulin resistance Excessive hepatic glucose production Impaired insulin secretion Impaired incretin effect
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Fasting and postload glucose levels, insulin sensitivity and insulin secretion before the diagnosis of T2DM (Whitehall II study) Tabak AG. et al. Lancet. 373:2215-21, 2009 Jun 27.
Fasting glucose
Insulin sensitivity
Postload glucose
Insulin secretion 50
At fasting plasma glucose >6.4 mmol/l first phase insulin response is absent FBG: 6.4 mmo/l 115 mg/dl
Brunzell JD, J Clin. Endoc Metab 42:22, 1976
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The molecular basis of insulin resistance (2007)
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a, Serine residues of IRS-1(S) b, Tyrosine residues of IRS-1 and (Y)
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Factors of insulin sensitivity • Genetics (50%, ethnic difference) • Visceral obesity (25%; adipocytokines: TNF-α, IL-6; NEFA, AG; PPAR-γ) • Physical activity (25 %; acute, chronic) • Age • Food (CH↑, fat↓,cytokine production↓) • AT II 54
Consequences of insulin resistance Lipids
Lipolysis ↑
NEFA ↑ Dyslipidemia Dyslipidemia Hyperglycemia
Liver
VLDL ↑ HGP ↑
Muscle
Glucose uptake ↓ Hyperglycemia
Endothel NO production ↓ Endothel dysfunction Heart Glucose uptake ↓ Metabolic disturbance 55
Effects of ectopic fat deposition
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Difference between T1 and T2DM T1DM Positive family - (+) history Clinical symptoms thin, sypmtoms +, ketonuria + Other diseases Antibodies (GADA)
autoimmune (thyroid, celiac) +
T2DM + obes, sypmtoms –, ketonuria metabolic syndome, CVD -
C-peptide- (insulin-) level
low/normal
normal/high/low
HLA association
DR3-DQ2; DR4-DQ8
58 no (TCF7L2)
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Other types of diabetes mellitus Monogenic forms • MODY (maturity onset diabetes of the young): mutations of the glucokinase, the HNF genes – beta cell failure, autosomal dominant inheritance early onset of diabetes (< 25 years) family accumulation (3 generations). • MIDD (maternally inherited diabetes and deafness): mutation of the mitochondrial gene, mostly A3243G (adenin-guanin change at position 3243). Progressive beta-cell failure. Metformin contraindicated! • Neonatal diabetes: diabetes onset in the first 60 6 months (up to 1 year)
Genetic classification of neonatal diabetes
(Kir6.2)
(SUR1)
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GLP1 GLP1 receptor
NDM
Adenyl cyclase CAMP PKA
MODY
MODY mtA3243G MIDD 62 Florez J.C.: Diabetologia, 2008, 51, 1100-1110.
KCNJ11 gén
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Other types of diabetes mellitus Monogenic forms • MODY (maturity onset diabetes of the young): mutations of the glucokinase, the HNF genes – beta cell failure, autosomal dominant inheritance early onset of diabetes (< 25 years) family accumulation (3 generations). • MIDD (maternally inherited diabetes and deafness): mutation of the mitochondrial gene, mostly A3243G (adenin-guanin change at position 3243). Progressive beta-cell failure. Metformin contraindicated! • Neonatal diabetes (NDM) 65
Genetic classification of MODY (Diabetes 57:2889, 2008)
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Other types of diabetes mellitus Monogenic forms • MODY (maturity onset diabetes of the young): mutations of the glucokinase, the HNF genes – beta cell failure, autosomal dominant inheritance early onset of diabetes (< 25 years) family accumulation (3 generations). • MIDD (maternally inherited diabetes and deafness): mutation of the mitochondrial gene, mostly A3243G (adenin-guanin change at position 3243). Progressive beta-cell failure. Metformin contraindicated! • Neonatal diabetes 68
1. Family with MIDD
GM/I
ND
10% NGT
15% ?DM
10% T2DM
M/I
A/I
ND
ND
ND
ND
15% T1DM
P/I
S2/I
5% T2DM
S1/I
2. Family
10% T2DM
ND
ND
ND
ND
ND
ND
M/II 30% LADA P/II
Hosszúfalusi…Pánczél, DMRR 25:127, 2009 69
Other specific types • Diseases of pancreas → insulin treatment • Endocrinopathies: Cushing syndrome, acromegaly, hyperthyroidism, phaeocromocytoma • Drug or chemical induced: - steroid induced diabetes ! 70
Clinical features
T1DM
T2DM Etiology autoantibodies, C-peptide, genetics
T2DM
Other types 1-2 % (known genetics)
T1DM (> 5 %) 71
Gestational diabetes (GDM) (ADA 2015) • Diagnosed during pregnancy • Test for undiagnosed DM at first prenatal visit in those with risk factors (HbA1c) • Screen!: 24-28 weeks of gestation, 75 g OGTT • Screen women with GDM for persistent diabetes 6-12 weeks postpartum • GDM, T1DM, T2DM, other • Lifelong screening for diabetes at least every 3 years • GDM + prediabetes → metformin 72
Diagnostic criteria for GDM One-step strategy (ADA, 2015) • 24-28 weeks, without previous DM diagnosis • OGTT, 75 g, any of the following values • FBG ≥ 5.3 mmol/l (95 mg/dl) • 1 hour BG: ≥ 10.0 mmol/l (180 mg/dl) • 2 hour BG: ≥ 8.5 mmol/l (153 mg/dl) 73
